The blood borne mast cell progenitors (MCp) are agranular mononuclear cells that arise from the granulocyte-monocyte lineage in bone marrow (BM) and enter peripheral tissues by transendothelial migration for maturation into particular phenotypes. Little is known about the trafficking of MCp to peripheral tissues, but we have recently found that movement to the small intestine requires expression of the integrin alpha4137 and the chemokine receptor CXCR2. MCp in tissue can be recovered and enumerated by limiting dilution analysis and clonal expansion of the MC lineage with maturation. Using mouse strains null for the integrin proteins aE, beta2,and beta7 and for intercellular adhesion molecule (ICAM)-1, and the chemokine receptors CXCR2, CCR3, and CCR5, we found that the intestine but not the lung, spleen, or BM was selectively deficient in MCp from the beta7 integrin and CXCR2 null strains. The fact that MCp were normal in the strains null for the recombinase activating gene (RAG)-2, either alone or in combination with the interleukin-receptor common gamma chain gene indicated that their selective homing to the intestine was innate. When normal mice were rendered deficient in MCp by sublethal irradiation and reconstituted with normal BM, blocking monoclonal antibody (mAb) to alpha4, beta7or a combinatorial epitope on alpha4beta7 integrins or to mucosal addressin cellular adhesion molecule (MAdCAM)-1 was inhibitory, indicating that transendothelial migration involved the interaction between alpha4beta7 integrin and MAdCAM-1. Similarly, when normal mice were rendered MCp-deficient by sublethal irradiation, BM from normal donors but not that from CXCR2 null donors restored the intestinal MCp, confirming the role of CXCR2 in intestinal homing of MCp. We hypothesize that the prerequisite selectin, integrin, and chemokine pathways by which MCp home will be tissue-specific, that inflammation will introduce additional pathways, and that tissue MCp can be defined by membrane markers so that their in situ distribution and maturation can be characterized. The aims of this proposal are to define the prerequisite adhesion and chemokine pathways required for homing to lung, to identify the additional pathways recruited to increase the MCp supply in lung and intestine after aerosol antigen-induced inflammation in sensitized normal and null strains, and to characterize the tissue MCp by membrane markers so as to allow their in situ identification.